Abstract
Forming an embryo from a zygote poses an apparent conflict for epigenetic regulation. On the one hand, the de novo induction of cell fate identities requires the establishment and subsequent maintenance of epigenetic information to harness developmental gene expression. On the other hand, the embryo depends on cell proliferation, and every round of DNA replication dilutes preexisting histone modifications by incorporation of new unmodified histones into chromatin. Here, we investigated the possible relationship between the propagation of epigenetic information and the developmental cell proliferation during Xenopus embryogenesis. We systemically inhibited cell proliferation during the G1/S transition in gastrula embryos and followed their development until the tadpole stage. Comparing wild-type and cell cycle-arrested embryos, we show that the inhibition of cell proliferation is principally compatible with embryo survival and cellular differentiation. In parallel, we quantified by mass spectrometry the abundance of a large set of histone modification states, which reflects the developmental maturation of the embryonic epigenome. The arrested embryos developed abnormal stage-specific histone modification profiles (HMPs), in which transcriptionally repressive histone marks were overrepresented. Embryos released from the cell cycle block during neurulation reverted toward normality on morphological, molecular, and epigenetic levels. These results suggest that the cell cycle block by HUA alters stage-specific HMPs. We propose that this influence is strong enough to control developmental decisions, specifically in cell populations that switch between resting and proliferating states such as stem cells.
Highlights
Different cell types are distinguished by specific chromatin states, which help to target DNAbinding factors to specific genomic regions
Establishing and maintaining the epigenetic information of covalent histone modifications faces a fundamental problem in proliferating cells, i.e., a 2-fold replicational dilution of preexisting histone marks during S phase needs to be matched by the biological kinetic rates of the enzymes decorating the chromatin landscape
While one might assume that evolution has ensured a robust balance between dilution and writing of histone posttranslational modification of histone (PTM), which adequately meets the physiological requirements of cells to acquire and maintain gene expression profiles and genome stability, recent work has indicated that this balance is delicate and could provide a resource for epigenetic regulation [51,52,53,54]
Summary
Different cell types are distinguished by specific chromatin states, which help to target DNAbinding factors to specific genomic regions. Covalent posttranslational modifications of histones (PTMs) contribute to these states in a pivotal manner [1]. The most abundant and functionally studied histone modifications are methylation (me), acetylation (ac), and phosphorylation (Ph), many other modifications have been reported [2]. Active chromatin domains are characterized by a distinct array of histone marks.
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